Effect of amiloride on lithium-induced chronic nephropathy.

Twenty percent of the patients on chronic lithium treatment develop a chronic
and sometimes progressive nephropathy (1,2). At a certain point the question
arises whether the use of lithium must cease to prevent progression of the
nephropathy. Data concerning the effect of ending lithium-use on the
progression of nephropathy related to chronic lithium-use are scarce.
In a group of 24 patients Lepkifker et al. found a mean plasma creatinine of
176 umol/l (values between 132 and 339 umol). In 12 patients decreasing the
lithiumdosage resulted in a reduction of plasma creatinine levels tot values in
the upper end of the normal interval. In three patients the plasma creatinine
concentration did not change. In 9 patients however the plasma creatinine
concentration continued to increase in spite of cessation of the use of lithium
(3). Presne et al. found that when lithium-use was stopped, the
creatinine-clearance improved in 5 out of 7 patients, when the level of the
creatinine clearance at that point was above 40 ml/min. In a group of 18
patients with a creatinine clearance lower than 40 ml/min, however, in 12
patients the creatinine clearance went on deteriorating, in spite of stopping
lithium (4).
Markowitz et al. found the nephropathy to be irreversible and progressive when
the plasma creatinine concentration at the time of stopping lithium was 220
umol/l or higher (5). Gitlin et al. recommend tot cease the use of lithium at
plasma creatinine levels ~140 umol/l, however without giving sufficient direct
evidence (6). Data mentioned above seem to suggest that amelioration or
stabilisation of renal function might still be obtained when lithium is stopped
at a plasma creatinine concentration of 150- 200 umol/l. Lithium remains first
choice in the maintenance treatment of bipolar disorders (7) and is proven to
be more effective than e.g. carbamazepine (8). Consequences of stopping lithium
may be quite substantial. Other psychotropic drugs tend to be less effective,
especially in bipolar depression, consequently resulting in temporary or
permanent psychiatric instability (9). Furthermore, evidence has been found
that lithium decreases attempts at suicide and suicide itself (10). Prevention
of lithium induced nephropathy whilst continuing the use of lithium would thus
prove to be a huge advantage.

The renal toxicity of lithium is in all probability a result of reabsorption of
lithium in the collecting ducts of the kidney. In perfusion of isolated
cortical collecting ducts, lithium administered from the luminal side prevents
the effect of antidiuretic hormone (ADH) on the transport of water (11). In
animals the administration of lithium causes a decrease in the concentrating
capacity of the kidney within the hour (12,13). Pretreatment with amiloride
prevents this effect of lithium (12). The above mentioned seems to suggest that
lithium is transported through amiloride-sensitive luminal sodiumchannels in
the collecting ducts and also that accumulation of lithium in these cells
interferes with the effect of ADH on renal water transport. Micropuncture
studies in rats directly confirmed the existence of amiloride- sensitive
lithiumtransport in the distal nephron(14). In vitro studies in skin and
bladder of amphibians confirm that lithium transport uses a mechanism that is
capable of transporting lithium as well as sodium and that can be put to a stop
by amiloride (15,16). In rats a toxic dosage of lithium causes necrosis of
distal nephron cells within the hour (17). Plasma lithiumconcentrations within
the therapeutic range bring on swelling of the cells in the cortical collecting
ducts of the rat kidney within 3 days. After 7 days cellular hyperplasia is
evident and elevated DNA-synthesis can be shown in autoradiography (18).
Another rat-study showed dilatation and cell proliferation in the collecting
ducts after three weeks, together with polyuria and polydipsia (19). In rats a
16- week exposure to lithium shows serious structural changes (interstitial
fibrosis with dilatation and development of cysts in the distal nephron and
tubular atrophy), together with a reduction of the glomerular filtration rate
and renal concentrating capacity (20).
Patients that started lithium-treatment recently, developed a unique, specific
lesion in distal tubuli and collecting ducts after just a few months of therapy
(22). This 'acute' lesion in humans is identical to that seen in laboratory
animals after lithium administration for several months. Patients treated with
lithium during several years show both this 'acute' distal lesion and a chronic
lesion including tubular atrophy, interstitial fibrosis and glomerular
sclerosis. The latter suggests dat early distal lesions precede the chronic
tubulo-interstitial nephritis.
Together the mentioned data suggest that amiloride- sensitive lithium transport
is at the base of the continuum of early and late nephrotoxic effects of
lithium. In this respect it is relevant that in patients on chronic lithium and
with renal diabetes insipidus, amiloride at least partly reduces polyuria and
polydipsia (23). This implies that during continued use of lithium there is a
still reversible nephrotoxic component which can be brought to a halt by
amiloride.
Similarly it might be possible that amiloride could stop the progression of
chronic tubulo- interstitial nephritis, but concerning this no data are
available.
Our hypothesis is that the ongoing use of lithium combined with amiloride,
which protects the cells of the distal nephron from accumulation of lithium,
produces the same result as stopping the use of lithium.

References.
1. Boton R, Gaviria M, Batlle DC.: Prevalence, pathogenesis, and treatment of
renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis.
1987 Nov;10(5):329-45.
2. van Gerven HA, Boer WH. Chronische nierfunctiestoornissen bij gebruik van
lithium. Ned Tijdschr Geneeskd. 2006 Aug 5;150(31):1715-8.
3. Lepkifker E, Sverdlik A, Iancu I, Ziv R, Segev S, Kotler M. : Renal
insufficiency in long-term lithium treatment. J Clin Psychiatry. 2004
Jun;65(6):850-6.
4. Presne C, Fakhouri F, Noel LH, Stengel B, Even C, Kreis H, Mignon F,
Grunfeld JP.: Lithium-induced nephropathy: Rate of progression and prognostic
factors. Kidney Int. 2003 Aug;64(2):585-92.
5. Markowitz GS, Radhakrishnan J, Kambham N, Valeri AM, Hines WH, D'Agati VD.
: Lithium nephrotoxicity: a progressive combined glomerular and
tubulointerstitial nephropathy. J Am Soc Nephrol. 2000 Aug; 11(8):1439-48.
6. Gitlin M.: Lithium and the kidney: an updated review. Drug Saf. 1999
20(3):231-243.
7. Nolen, W.A., Kupka, R.W., Schulte, P.F.J., Knoppert- van der Klein, E.A.M.,
Honig, A., Reichart, C.G., Goossens, P.J.J., Daemen, P., Ravelli, D.J. (2008).
Richtlijn Bipolaire Stoornissen, Nederlandse Vereniging voor Psychiatrie,
Utrecht.
8. Hartong EG, Moleman P, Hoogduin CA, Broekman TG, Nolen WA; LitCar Group.
Prophylactic efficacy of lithium versus carbamazepine in treatment-naive
bipolar patients. J Clin Psychiatry. 2003; 64: 144-151.
9. Hartong EG (2006). Recidiefpreventie van bipolaire stoornis.
Geneesmiddelenbulletin 40, 61-69
10. Baldessarini RJ, Tondo L, Davis P, Pompili M, Goodwin FK, Hennen J.
Decreased risk of suicides and attempts during long-term lithium treatment: a
meta-analytic review. Bipolar Disord. 2006; 8: 625-839.
11. Cogan E, Abramow M. Inhibition by lithium of the hydroosmotic action of
vasopressin in the isolated perfused cortical collecting tubule of the rabbit.
J Clin Invest. 1986 May;77(5):1507-14.
12. Webb RK, Woodhall PB, Tisher CC, Robinson RR. Acute effects of lithium on
the renal concentrating mechanism in a primate. Am J Physiol. 1975 Mar;228(3):
909-14.
13. Harris CA Jenner FA Some aspects of the inhibition of the action of
antidiuretic hormone by lithium ions in the rat kidney and bladder of the toad
Bufo Marinus. Brit J Pharmacol 44:223-232, 1972
14. Fransen R, Boer WH, Boer P, Koomans HA. Amiloride-sensitive lithium
reabsorption in rats: a micropuncture study. J Pharmacol Exp Ther. 1992
Nov;263(2):646-50.
15. Leblanc G. Mechanism of lithium accumulation in the isolated frog skin
epithelium. Pflugers Arch. 337: 1-18, (1972).
16. Herrera FC. Inhibition of lithium transport across toad bladder by
amiloride. Am. J. Physiol. 222 (2): 499-502 (1972).
17. 9. Levine S, Saltzman A, Katof B, Meister A, Cooper TB. Prevention of
lithium nephrotoxicity in a novel one-hour model in rats. Psychopharmacology
(Berl). 1998 Jul;138(1):34-9.
18. 10. Jacobsen NO, Olesen OV, Thomsen K, Ottosen PD, Olsen S. Early changes
in renal distal convoluted tubules and collecting ducts of lithium treated
rats: light microscopy, enzyme histochemistry, and 3[H]-thymidine
autoradiography. Lab Invest 46:298-305, 1982.
19. Kling MA, Fox JG, Johnston SM, Tolkoff-Rubin NE, Rubin RH, Colvin RB.
Effects of long-term lithium administration on renal structure and function
in rats. A distinctive tubular lesion. Lab Invest. 1984 May;50(5):526-35.
20. Ottosen PD, Sigh B, Kristensen J, Olsen S, Christensen S. Lithium induced
interstitial nephropathy associated with chronic renal failure. Acta Path
Immunol Scand 92: 447-454, 1984.
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progressive renal lesions induced by lithium. Kidney Int. 1986 Apr;29(4):875-81.
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lithium. Lancet, 7;1310 , 1978
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(1) to establish the effect of adding amiloride to lithium- treatment on the
progression of renal insufficiency in patients with lithium- nephropathy
(2) to answer the question whether adding amiloride to the use of lithium has
the same effect as stopping lithium.

Patients.
Patients on chronic lithium therapy and with a progressive renal insufficiency,
defined as a yearly rise in plasma creatinine of at least 10 umol/ l with a
correlation coefficient of at least 0,85 and a maximum plasma creatinine
concentration of 200 umol/l. Starting with a normal plasma creatinine
concentration, this would imply a reduction of the creatinine clearance of ~10%
per year. When these conditons are met there is a fair prospect of
reversibility and the result of an intervention on the development of the
plasma creatinine concentration can well be studied. At inclusion patients
should be normotensive, if necessary with antihypertensive medication.

- Group size estimation.
Our hypothesis is that the slope in the course of the plasma creatinine
concentration wil be reduced from 20 +/- 13 umol per year to 10 +/- umol per
year. Using a paired T-test this amounts to 15 patients per group.

- Protocol
Patients will be excluded that are unable to give informed consent.

- Randomisation:
Group I: stops lithium (actual dosage discontinued in three months, reduction
with 1/3 every month)
Group II continues lithium in combination with amiloride.

- choice of alternative/ other moodstabiliser at the discretion of the
psychiatrist (group I)

- Group II: administration of amiloride (20 mg once daily), together with
lithium. Reduction of the lithiumdosage with 1/3 at the start of amiloride.
Titration of the lithiumdosage till the usual target plasma lithium
concentration is achieved at two consecutive weekly measurements. During this
phase, plasma potassium will be checked weekly. In case of values > 5,5 mmol/l,
an adequate dose of sodiumpolystyrenesulphate (Resonium) will be added to the
medication. Since Resonium inhibits lithium- resorption the lithiumdosage must
be elevated under regular check ups of the plasma lithium concentration.

- measurements at inclusion:
At start of the study (T 0, still at full lithium dosage) : biochemistry. MDRD
(eGFR- formula). Urine- analysis to exclude other causes of renal pathology
(sediment, micro- albuminuria, proteinuria, osmolarity), ECHO of the kidney's .
Delta decline of plasma creatinine. Bloodpressure. Co- medication. Comorbidity.
Psychiatric history, duration of lithium-use.

Interim- analysis
Analysis of our own (limited) cohort/ patientgroup (figure 1) showed an effect
of stopping lithium within a period of 6 months. After cessation of
lithium-use, or amiloride-addition in continued use of lithium
plasma-kreatinineconcentration will be measured at quarterly intervals. In
group II patients will cease using lithium (and amiloride) if no change is
visible in the course of the plasma creatinineconcentration (at least cutting
in half the slope of the plasma creatinine concentration) within 9 months.

Ending the study:
see interim-analysis.

Follow-up:
Group I (lithium stop): from the start of the reduction of the lithiumdosage,
the plasma- creatinine concentration (and eGFR) and bloodpressure will be
measured at quarterly intervals during a period of two years, as well as the
psychiatric condition.

Group 2 (lithium with amiloride): from the start of the reduction of the
lithiumdosage, the plasma- creatinine concentration (and eGFR), potassium- and
lithiumconcentrations and bloodpressure will be measured at quarterly intervals
during a period of two years, as well as the psychiatric condition.

Group I: administration of amiloride (20 mg once daily), together with lithium.
Reduction of the lithiumdosage with 1/3 at the start of amiloride. Titration of
the lithiumdosage till the usual target plasma lithium concentration is
achieved at two consecutive weekly measurements. During this phase, plasma
potassium will be checked weekly. In case of values > 5,5 mmol/l, an adequate
dose of sodiumpolystyrenesulphate (Resonium) will be added to the medication.
Since Resonium inhibits lithium- resorption the lithiumdosage must be elevated
under regular check ups of the plasma lithium concentration.

There is no burden which is considered to be greater than that of undergoing
regular check ups which are usually done during lithium use.

Risk:

- there is a slight risk of elevated potassium levels during the start of
amiloride. This will be anticipated by checking the blood potassium level 2-3
times during this period. If necessary, sodiumpolystyrenesulphate (Resonium)
will be administered to reduce the potassium level. Since
sodiumpolystyrenesulphate may lower lithium reabsorption, the dose of lithium
may have to be increased. In this case, the plasma lithium concentration will
be monitored more frequently.

- if there is no favourable effect of the intervention, renal function will
continue to deteriorate in the lithium - amiloride group. Since lithium
nephropathy progresses very slowly however, postponing the stopping of lithium
(with its potentially severe psychiatric repercussions) will result in a minor,
clinically irrelevant loss of renal function.